Autoimmune Regulator Deficiency Results in a Decrease in STAT1 Levels in Human Monocytes

Abstract

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by biallelic autoimmune regulator (AIRE) mutations that manifests with chronic mucocutaneous candidiasis (CMC) and autoimmunity. Patients with STAT1 gain-of-function (GOF) mutations also develop CMC and autoimmunity; they exhibit increased STAT1 protein levels at baseline and STAT1 phosphorylation (pSTAT1) upon interferon (IFN)-γ stimulation relative to healthy controls. AIRE interacts functionally with a protein that directly regulates STAT1, namely protein inhibitor of activated STAT1, which inhibits STAT1 activation. Given the common clinical features between patients with AIRE and STAT1 GOF mutations, we sought to determine whether APECED patients also exhibit increased levels of STAT1 protein and phosphorylation in CD14+ monocytes. We obtained peripheral blood mononuclear cells from 8 APECED patients and 13 healthy controls and assessed the levels of STAT1 protein and STAT1 tyrosine phosphorylation at rest and following IFN-γ stimulation, as well as the levels of STAT1 mRNA. The mean STAT1 protein levels in CD14+ monocytes exhibited a ~20% significant decrease in APECED patients both at rest and after IFN-γ stimulation relative to that of healthy donors. Similarly, the mean peak value of IFN-γ-induced pSTAT1 level was ~20% significantly lower in APECED patients compared to that in healthy controls. The decrease in STAT1 and peak pSTAT1 in APECED patients was not accompanied by decreased STAT1 mRNA or anti-IFN-γ autoantibodies; instead, it correlated with the presence of autoantibodies to type I IFN and decreased AIRE−/− monocyte surface expression of IFN-γ receptor 2. Our data show that, in contrast to patients with STAT1 GOF mutations, APECED patients show a moderate but consistent and significant decrease in total STAT1 protein levels, associated with lower peak levels of pSTAT1 molecules after IFN-γ stimulation.

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

“…A small proportion of APECED patients develop recurrent infections by herpetic viruses such as HSV and VZV (~15%, Lionakis, unpublished observations), without an obvious correlation between the titers or neutralizing potential of type I interferon AAbs or the levels of STAT1 . APECED patients have also sporadically been reported to develop Giardia intestinal infections, although the mechanisms for this susceptibility remain elusive …”

The Role of AIRE in the Immunity Against Candida Albicans in a Model of Human Macrophages

“…Autoimmune regulator is essential for proper T cell development and selection in the thymus. While Dectin-1 and CARD9 are expressed in many cell types, studies have shown that AIRE is expressed in peripheral lymphoid tissues, monocytes, and dendritic cells and that it participates in extrathymic functions ( 23 , 24 , 40 ). APECED patients produce variable titers of autoantibodies against IL-17A, IL-17F, or IL-22 associated with CMC ( 17 , 18 , 26 ).…”

“…However, some patients are susceptible to CMC without these autoantibodies ( 18 ), suggesting that other factors may involved in CMC in these patients. AIRE deficiency has been associated with failure in building a proper immune response by monocytes ( 23 , 24 , 41 ). Recently, it has been shown that monocytes from APECED patients have a decrease in IFN-γR2 and STAT1 protein levels that are associated with lower levels of phosphorylated STAT1 molecules after IFN-γ stimulation ( 24 ).…”

“…AIRE deficiency has been associated with failure in building a proper immune response by monocytes ( 23 , 24 , 41 ). Recently, it has been shown that monocytes from APECED patients have a decrease in IFN-γR2 and STAT1 protein levels that are associated with lower levels of phosphorylated STAT1 molecules after IFN-γ stimulation ( 24 ). Another study reported failure of the immune response to C. albicans , including a dysregulation of IL-23p19 production in monocytes from APECED patients stimulated with C. albicans ( 41 ).…”

“…However, many studies have shown that AIRE is expressed in extra-thymic cells. These include peripheral lymphoid tissues and monocytes and dendritic cells, and there is evidence that AIRE can modulate the inflammatory response ( 22 – 24 ).…”